The goal of the proposed research is an understanding of neoplastic transformation through the study of viral and cellular onc genes and of the oncogenic phenotype. We will identify new onc genes using newly isolated, rapidly transforming retroviruses and will define their place and function in the network of cellular regulatory genes. The new onc genes will be characterized by determining their nucleotide sequence and isolating the corresponding protein product. The structure and expression of homologous cellular loci will be studied. Investigations of function will concentrate on the properties of the new onc proteins and on sequence comparisons with known cellular genes. We will also search for a system in which cellular sequences are acquired by a retrovirus genome with a frequency high enough to allow mechanistic analysis. Specific cellular functions and targets in the process of oncogenic transformation will be searched for and identified by cell mutants that are temperature-sensitive for the transformed phenotype. In a different approach to this same question, differentiated cell types that are refractory to the action of an expressed onc gene will be studied. We also plan to analyze stage-specific differentiation markers in the course of virus induced leukemia and relate changes in the expression of these markers to onc gene action. In an effort to explain the origin of spontaneous nonviral tumors, we will look for activated onc genes in tumors and tumor cell lines that are free of rapidly transforming retroviruses. All these investigations will contribute to our knowledge of molecular mechanisms regulating cell growth and differentiation.